Nasal anti-CD3 antibody ameliorates lupus by inducing an IL-10-secreting CD4+ CD25- LAP+ regulatory T cell and is associated with down-regulation of IL-17+ CD4+ ICOS+ CXCR5+ follicular helper T cells.
Lupus is an Ab-mediated autoimmune disease. One of the potential contributors to the development of systemic lupus erythematosus is a defect in naturally occurring CD4(+)CD25(+) regulatory T cells. Thus, the generation of inducible regulatory T cells that can control autoantibody responses is a potential avenue for the treatment of systemic lupus erythematosus. We have found that nasal administration of anti-CD3 mAb attenuated lupus development as well as arrested ongoing lupus in two strains of lupus-prone mice. Nasal anti-CD3 induced a CD4(+)CD25(-)latency-associated peptide (LAP)(+) regulatory T cell that secreted high levels of IL-10 and suppressed disease in vivo via IL-10- and TFG-beta-dependent mechanisms. Disease suppression also occurred following adoptive transfer of CD4(+)CD25(-)LAP(+) regulatory T cells from nasal anti-CD3-treated animals to lupus-prone mice. Animals treated with nasal anti-CD3 had less glomerulonephritis and diminished levels of autoantibodies as measured by both ELISA and autoantigen microarrays. Nasal anti-CD3 affected the function of CD4(+)ICOS(+)CXCR5(+) follicular helper T cells that are required for autoantibody production. CD4(+)ICOS(+)CXCR5(+) follicular helper T cells express high levels of IL-17 and IL-21 and these cytokines were down-regulated by nasal anti-CD3. Our results demonstrate that nasal anti-CD3 induces CD4(+)CD25(-)LAP(+) regulatory T cells that suppress lupus in mice and that it is associated with down-regulation of T cell help for autoantibody production.
Wu
Henry Yim
HY
Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Quintana
Francisco J
FJ
Weiner
Howard L
HL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology*; D015704:CD4 Antigens / Q000096:biosynthesis; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006131:Growth Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10 / Q000378:metabolism*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D053779:Latent TGF-beta Binding Proteins / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB; D009297:Nasal Mucosa / Q000276:immunology*; D054380:Receptors, CXCR5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D015704:CD4 Antigens; C513179:CXCR5 protein, mouse; D006131:Growth Inhibitors; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D053779:Latent TGF-beta Binding Proteins; D054380:Receptors, CXCR5; D016753:Interleukin-10